The present invention relates to a medicament for treatment or prevention of diastolic dysfunction, particularly to those containing 2-(1-piperazinyl)-5-methylbenzenesulfonic acid derivative or its salt, or hydrate or solvate thereof as the active ingredient.
The heart is one of the most important organs in organisms that serves as a pump for propelling blood into and through the arteries. It has two functions: diastolic and systolic functions. In the normal heart, the ventricular chambers are actively filled with the blood returned from the veious system during a diastole. In contrast, the blood filling the ventricular chamber will be ejected through aorta, against the pressure gradient, into systemic circulation during a systole.
On the other hand, cardiac dysfunction in diseased hearts may reduce cardiac output, resulting in insufficient systemic circulation. Although a living body may try to maintain these functions to some extent, by its compensatory mechanism, continued cardiac dysfunction could result in heart failure at least.
Conventionally, xe2x80x9cheart (cardiac) failurexe2x80x9d has often been regarded to be the same as xe2x80x9csystolic dysfunctionxe2x80x9d. In fact, however, it has been reported that as much as 40% of patients exhibiting xe2x80x9cheart failurexe2x80x9d had normal systolic function assessed by ejection fractions. Moreover, it has also been reported that 20% or more of patients with apparent xe2x80x9csystolic dysfunctionxe2x80x9d exhibited no xe2x80x9cheart failurexe2x80x9d (Pouleur H. et al.: Focus on diastolic dysfunction: a new approach to heart failure therapy. Br. J. Clin. Pharmacol. 28: 41s, 1989). Recently, it has been accepted that diastolic dysfunction, insufficient relation of the left ventricle, is intimately associated with heart failure.
The more the concept and importance of diastolic dysfunction, in addition to systolic dysfunction, have been recognized for the understanding of pathophysiology of cardiac functions, the more the role of diastole dysfunction in pathophysiology of heart failure has been focused on.
Taken these into consideration, ACC(American College of Cardiology)/AHA(American Heart Association) Task Force (U.S.A.) stated, in xe2x80x9cACC/AHA Task Force Report; Guidelines for the Evaluation and Management of Heart Failure. Circulation. 92:2764-2784, 1995xe2x80x9d, that heart failure caused by diastolic dysfunction should be distinguished from one caused by systolic dysfunction by using Doppler-two-dimensional echocardiography or radionuclide imaging, or by cardiac catheterization, that it is preferable to treat heart failure patients distinctively depending on their cardiac function, systolic dysfunction or diastolic dysfunction.
In fact, however, there is no medical therapy that is effective for treatment of diastolic dysfunction by direct effects on cardiac muscles (Katz AM: Interplay between inotropic effects of cyclic adenosine monophosphate on the myocardial cell. Circulation (Suppl) 82: 1, 1990).
Diastolic dysfunction can be found not only in patients with heart failure but also in those with cardiac dysfunction induced by various causes such as hypertrophy induced by pressure overload and volume overload, sepsis, systemic shock, post-ischemic myocardium, idiopathic cardiomyopathy and diabetic cardiomyopathy.
Clinically, diastolic dysfunction has been recognized as important issue in ICU patients with cardiogenic or non-cardiogenic acute circulatory failure.
Recently, as the clinical importance of diastolic dysfunction has become more apparent and commonly understood, much attention has been paid to the hypothesis that the abnormal Ca2+ uptake by sarcoplasmic reticulum, an organella in cardiac myocytes, commonly plays the main role in pathophysiology of xe2x80x9cdiastolic dysfunctionxe2x80x9d.
In short, contraction and relaxation of cardiac muscle are dependent on cytosolic free Ca2+ concentration. The Ca2+ released from sarcoplasmic reticulum into cytoplasma during a systole is uptaken by the sarcoplasmic reticulum during a diastole. In diseased hearts, the Ca2+ uptake ability is reduced, resulting in higher level of intracellular Ca2+ during a diastole. Ca2+ uptake into sarcoplasmic reticulum is carried out by Ca2+ pump referred to as Ca2+-ATPase present on the membrane of endoplasmic reticulum. It has been reported that such reduction in Ca2+ uptake ability is accompanied by reduction in Ca2+-ATPase activity in various diseased hearts (Angel Zarain-Herzberg, Nasir Afzal, Vijayan Elimban and Naranjan S. Dhalla: Decreased expression of cardiac sarcoplasmic reticulum Ca2+ pump ATPase in congestive heart failure due to myocardial infarction. Molecular and Cellular Biochemistry 163/164: 285-290, 1996, Ulrich Schmidt, Maria Carles, Roger H. Hajjar, Thomas G. DiSalvo, Marc J. Semigran, G. William Dec, Jagat Narula, Ban-An Khaw, JudithK. Gwathmey: Abnormal Sarcoplasmic Reticulum Ca2+ Activity and Uptake in Human Heart Failure. J. Am. Coll. Cardiol. 27 (Suppl A): 56A, 1996, D. Lagadic-Gossmann, K. J. Buckler, K. Le Prigent and D. Feuvray: Altered Ca2+ handling in ventricular myocytes isolated from diabetic rats. Am. J. Physiol. 270: H1529-H1537, 1996).
Now, xe2x80x9cdiastolic dysfunctionxe2x80x9d is regarded as pathophysiological conditions underlying heart diseased with reduced sarcoplasmic reticulum Ca2+-ATPase as well as those that are not always categorized according to the conventional definition of heart disease.
Aminobenzenesulfonic acid derivatives are known to inhibit overaccumulation of intracellular calcium ions in the cardiac muscle or the vascular smooth muscle, i.e., inhibit excess influx of extracellular calcium ions in disease heart (Japanese Patent Application Laid-Open No. 3-7263). It has been disclosed that such compounds may be an effective agent for prevention or treatment of ischemic heart disease, heart failure, hypertension and arrhythmia by inhibiting or reducing myocardial damages or defects in cardiac excitation conducting system (Japanese Patent Application Laid-Open No. 3-7263 and Japanese Patent Application Laid-Open No. 4-139127). However, any of these publications neither suggested nor stated that 2-(1-piperazinyl)-5-methylbenzenesulfonic acid derivative or its salt, or hydrate or solvate thereof may be useful for prevention or treatment of abnormal intracellular Ca2+ handling, which could not be improved by any conventional techniques described above, mainly characterized by reduction in Ca2+ uptake ability of intracellular sarcoplasmic reticulum of myocardial cytoplasmic system, and may be useful for prevention or treatment of xe2x80x9cdiastolic dysfunctionxe2x80x9d in cardiac contraction/relaxation cycle due to such abnormal Ca2+ handling.
The object of the present invention is to provide a medicament for treatment or prevention of diastolic dysfunction.
The present inventors found, after intense studies to solve the above-described problems, that any compounds selected from the group comprising of 2-(1-piperazinyl)-5-methylbenzenesulfonic acid derivative or its salt, or hydrate or solvate thereof may provide preferable effects, i.e. preventing or treating the reduction in Ca2+ uptake ability of myocardial sarcoplasmic reticulum, suggesting that such compounds will improve diastolic function. Further, these compounds have been found to improve the myocardial motion as well. Based on these findings, the present inventors developed the present invention.
In summary, the present invention relates to a medicament for treatment or prevention of diastolic dysfunction, comprising 2-(1-piperazinyl)-5-methylbenzenesulfonic acid derivative or its salt, or hydrate or solvate thereof as the active ingredient.
Preferable examples of the present invention include a medicament for treatment or prevention of diastolic dysfunction, comprising 2-(1-piperazinyl)-5-methylbenzenesulforic acid derivative monohydrate as the active ingredient, particularly, (1) a medicament for treatment or prevention of diastolic dysfunction in patients with cardiogenic circulation failure comprising any of the active ingredients described above; and (2) a medicament for treatment or prevention of diastolic dysfunction in patients with non-cardiogenic circulation failure comprising any of the active ingredients described above.
Alternatively, another aspect of the present invention provides a method for treatment or prevention of reduction in Ca2+ uptake ability of cardiac sarcoplasmic reticulum by administering any medicaments described above to mammalians; a method for improving diastolic dysfunction; a method for improving reduced myocardial motility by virtue of such improvement of myocardial diastolic dysfunction by administering any medicaments described above to mammalians; and use of 2-(1-piperazinyl)-5-methylbenzenesulfonic acid derivative or its salt, or hydrate or solvate thereof for preparing the above-described medicaments.